Significant advances have been made in the early detection and treatment of breast cancer. Nevertheless, it is still the most common cancer and the second leading cause of cancer death among women in the U.S. The use of current chemopreventive agents, such as tamoxifen and raloxifene, has been limited by toxicity; in addition, they do not reduce the risk of ER negative breast cancer, which represents about one-third of invasive breast cancers and the more aggressive triple negative tumors.
Colon cancer, among other cancers, is a multifactor disease.
Breast cancer and colorectal cancer have been associated with mutations in 189 genes (average of 11 per tumor) (Liby et al., 2007).
There is an imperative need for agents with low toxicity for treating and inhibiting the development of breast cancer, colon cancer and other cancers. The optimal treatment for cancer most likely requires an agent or combination of agents that can correctly target multiple pathways (bioavailability) with minimal toxicity.
Rosemary contains multiple components including carnosic acid (CA), rosmarinic acid, carnosol (CS), caffeic acid, and ursolic acid, which contribute to the biological activity of rosemary and could provide effective synergy. Whole extracts and purified components isolated from rosemary have been shown to inhibit the in vitro and in vivo growth of breast cancer cells.
Carnosic acid, a polyphenolic diterpene (FIG. 1A), in particular, has shown anti-inflammatory, chemopreventive, and anticancer activity. In preclinical studies, vitamin D and carnosic acid showed synergistic growth inhibitory effects in leukemia models. Steiner et al. (Steiner, M, et al., “Carnosic acid inhibits proliferation and augments differentiation of human leukemic cells induced by 1,25-dihydroxyvitamin D3 and retinoic acid,” Nutr Cancer 2001; 41:135-44, incorporated by reference herein) found that carnosic acid potentiated the differentiating and antiproliferative effects of 1,25D3 in human myeloid leukemia cell lines HL60 and U937. Danilenko et al. (Danilenko, M. et al., “Carnosic acid and promotion of monocytic differentiation of tHL60-G cells initiated by other agents,” J Natl Cancer Inst. 2001; 93:1224-33, incorporated by reference herein) demonstrated that carnosic acid increased the expression of the VDR and augmented its DNA binding activity. Carnosic acid and 1,25D3 synergistically activated the Raf-MEK-ERK-p90RSK MAPK cascade in HL60 cell. Treatment of human myeloid leukemia cells with carnosic acid resulted in a decrease in the intracellular levels of reactive oxygen species (ROS). Moreover, combined treatment of leukemia-bearing mice with a vitamin D analog and rosemary extract resulted in normalization of white blood cell and differential counts and increased survival compared to untreated mice.
Carnosic acid has also been shown to exhibit synergy with curcumin. In KO and HL-60 human AML cells, nontoxic combinations of curcumin and CA resulted in synergistic growth inhibitory effects and significant apoptotic cell death involving the extrinsic and intrinsic apoptotic pathways. It is important that these agents did not alter the viability of normal human fibroblasts or proliferating and nonproliferating blood cells.
Recent studies pertain to the mode of action of CA and CS. Using microarray analysis, CA and CS have been shown to activate the ARE and stimulate glutathione metabolism, which inhibited the differentiation of mouse preadiocytes 3T3-11 cells to adipocyte. Thus CA may have potential to treat obesity related conditions. Further gene expression studies indicated that CA and CS protect cortical neurons (HT22 cells) by activating the Keap1/Nrf2 pathway, which induces phase 2 enzymes and subsequently enzymes involved in glutathione metabolism. In addition, CA has been shown to inhibit the function of the human drug efflux transporter P-glycoprotein (MDR1, ABCB1) and multidrug resistance protein 1 (MRP1, ABCC1).